The present invention relates to macrocyclic lactones, compositions, and methods of use.
Biological metabolites are the subject of ongoing structural characterization in the identification of new, structurally interesting, naturally occurring organic molecules, often with undetermined uses. Recently, biological metabolites have become an important area of intense focus in the search for new medicinal leads with potential applicability in a broad range of therapeutic indications including, for example, anti-infective and anti-cancer therapy. One particularly vast source of potential medicinally relevant metabolites are marine organisms. For example, sponges of the genus Haliclona (class Demospongiae, order Haplosclerida, family Haliclonidae) have been reported to produce a variety of secondary metabolites. Especially notable has been the production of alkaloids such as the polymeric halitoxin, the antitumor betacarbolines manzamine A, B and C, pupauamine and haliclonadiamine, antimicrobial and antifungal pentacyclic alkaloids, haliclamines A and B, and halicyclamine A, a tetracyclic diamine alkaloid. See Faulkner, J. Nat. Prod. Rep., 10, 497-539 (1993), and references cited therein; Parameswaran et al., Oceanogr. Indian Ocean, 417-420 (1992); Jaspars et al., J. Org. Chem., 59, 3253-3255 (1994); Venkateswarlu et al., J. Nat. Prod., 57, 1283-1285 (1994); Kobayashi et al., Tetrahedron, 51, 3727-3736 (1995); Zeng et al., Zhongguo Haiyang Yaowu, 14, 5-7 (1995) (Chem. Abstr., 123, 193621 (1995)); Shen et al., Chin. Pharm. J. (Taipei), 48, 1-10 (1996) (Chem. Abstr., 125, 82280 (1996)); and Charan et al., Tetrahedron, 52, 9111-9120 (1996). In addition, non-nitrogenous compounds, including tetrahydropyrans, alkylresorcinols, a tetrahydropyrone, sesquiterpenoid quinols, and enol sulfates have been found in Haliclona. However, none of these nonalkaloidal metabolites have been shown to have anticancer or cytotoxic activity.
Macrocyclic lactones are included among the classes of compounds identified from biological sources. For example, relatively simple fungal-derived orsellinic acid macrolides, lasiodiplodin (Aldridge et al., J. Chem. Soc. (C), 1623-1627 (1971)), which contain a 12-membered benzolactone ring with a methyl substituent at the ester methine, have been identified. Other relatively simple macrolides such as, for example, the 14-membered ring macrolide disclosed in Urry et al., Tetrahedron Lett., 3109-3114 (1966), have been identified. Some arguably more complex macrolides of biological origin have been reported to possess an enamine formamide residue, which residue can be found in the ulapualide-kabiramide-halichondramide-mycalolide-jaspisamide, and tolytoxin(scytophycin)-sphinxolide classes of macrolides. See Roesener and Scheuer, J. Am. Chem. Soc., 108, 846-847 (1986); Matsunaga et al., J. Am. Chem. Soc., 108, 847-849 (1986); Kernan and Faulkner, Tetrahedron Lett., 28, 2809-2812 (1987); Kernan et al., J. Org. Chem., 53, 5014-5020 (1988); Fusetani et al., Tetrahedron Lett., 30, 2809-2812 (1989); Rashid et al., J. Nat. Prod., 58, 1120-1125 (1995); Kobayashi et al., J. Nat. Prod., 56, 787-791 (1993); Carmeli et al., J. Nat. Prod., 53, 1533-1542 (1990); and D""Auria et al., Tetrahedron, 49, 8657-8664 (1993).
Numerous compounds have been isolated from tunicates of the genus Aplidium. Examples of metabolites previously reported include prenylated quinones from Aplidium sp., A. californicum, A. costellatum, and A. antillense. See Fenical, In: Food-Drugs from the Sea, Proceedings, 4th (Webber and Ruggieri, eds.), Marine Technology Society, 1974, pp. 388-394; Guella et al., J. Nat. Prod., 50, 621-626 (1987); Howard et al., Tetrahedron Lett., 4449-4452 (1979); Targett and Keeran, J. Nat. Prod., 47, 556-557 (1984); Benslimane et al., J. Nat. Prod., 51, 582-583 (1988)]; Fu et al., J. Am. Chem. Soc., 116, 12125-12126 (1994) (dimeric prenylated quinones from Aplidium longithorax); Carter and Rinehart, J. Am. Chem. Soc., 100, 7441-7442 (1978) (a sphingosine derivative from an Aplidium sp.); Arabshashi and Schmitz, Tetrahedron, 29, 1099-1102 (1988) (thiazole and imidazole metabolites from A. placiferum); Copp et al., Tetrahedron Lett., 30, 3703-3706 (1989) (1,2,3-trithiane derivatives from an Aplidium sp.); Kobayashi et al., J. Org. Chem., 59, 255-257 (1994) (alkaloids from an Aplidium sp. and A. pantherinium); Doi et al., Tetrahedron, 50, 8651-8656 (1994) (alkaloids from an Aplidium sp. and A. pantherinium); Carroll et al., Aust. J. Chem., 46, 825-832 (1993) (nucleosides from A. multiplicatum); Kim et al., J. Nat. Prod., 56, 1813-1816 (1993) (nucleosides from A. multiplicatum); and Rochfort et al., Aust. J. Chem., 49, 1217-1219 (1996) (chromenols from A. solidum).
Murray et al., Aust. J. Chem., 48, 1253-1266 (1995), discloses the isolation of aplidites A-G from an Aplidium sp.; however, there was no indication of biological activity of any kind, and subsequent investigations revealed that the structural assignment of the aplidites in Murray et al. (supra) may have been in error.
Among the numerous challenges faced by medicinal chemistry research, one of the most perplexing problems remains identifying new leads applicable in the chemotherapeutic treatment of cancers. Purely synthetic approaches toward the identification of novel anticancer agents are typically unsuccessful, partly due to the technological and human limitations inherent in laboratory synthesis. Although biological metabolites provide a vast resource of new structurally diverse chemical compounds, some of which have demonstrated biological activity, the therapeutic options for individuals suffering from cancer are tragically few.
Thus, there remains a need for anticancer compounds, pharmaceutical compositions, and methods of treating cancer. The present invention provides such compounds, compositions, and methods. These and other advantages of the present invention, as well as additional inventive features, will be apparent from the description of the invention provided herein.
The present invention provides a compound of the formula: 
wherein R1 and R2 are the same or different and are independently H, C1-C6 straight-chain or branched-chain saturated or unsaturated alkyl, aryl, R6CH2xe2x80x94, R6COxe2x80x94, or R6SO2xe2x80x94, wherein R6 is H, C1-C6 straight-chain or branched-chain saturated or unsaturated alkyl, or aryl; R3 is H, C1-C6 straight-chain or branched-chain saturated alkyl, aryl, an oxime, or an oxime methyl ether; at least one aromatic ring position is optionally substituted with a substituent selected from the group consisting of halo, nitro, amino, hydroxyl, thio, acyl, C1-C6 alkyl, and cyano; and Z is a contiguous linker comprising a chain of 7-10 atoms (including heteroatoms) which atoms, together with the five atoms beginning with the carbon of the aromatic ring in meta-relationship with OR1 and ending with the carbon directly attached to the alkyl oxygen of the lactone, which carbons are covalently bonded to either end of linker Z, integrally form a 12-15 membered ring; or a pharmaceutically acceptable salt, an ester, or a prodrug thereof.
The present invention also provides a composition which comprises a therapeutically effective amount of at least one compound of the present invention and a pharmaceutically acceptable carrier.
The present invention further provides a method of preventing or treating cancer which comprises administering to a patient in need thereof an anticancer effective amount of at least one compound of the present invention.